| 抄録 |
Although 80% of hepatocellular carcinomas（HCCs）arise in fibrotic livers, it remains elusive whether hepatic fibrosis promotes HCC. The link between fibrosis and HCC has been difficult to establish as virtually all fibrosis models induce inflammation or affect epithelial cells making it difficult to sort out the specific contribution of activated hepatic stellate cells（HSCs）to hepatocarcinogenesis. To determine whether HSC activation and liver fibrosis promote HCC, we developed a novel genetic mouse model of HSC activation in which the transcription factor Lhx2 is deleted. Lhx2 was selectively expressed in HSCs and efficiently deleted by Mx1-Cre and a novel HSC-specific Cre transgenic mouse, LRAT-Cre. Lhx2 deletion resulted in HSC activation with significantly increased expression of HSC activation markers, including Col1a1, TIMP1 and lysyl oxidase. Comparison of this genetic HSC activation model with BDL- and CCl4-induced HSC activation by microarray revealed concordant regulation of virtually all significantly up-or downregulated genes（p＜10-15）. Lhx2 deletion did not increase inflammation, liver injury, or progenitor/stem cell rendering this model suitable to evaluate links between HSC activation and HCC. Lhx2 deletion profoundly accelerated DEN-induced hepatocarcinogenesis with a 5-fold increase in tumor number（p＜0.01）and 2-fold increase in liver/body weight ratio（p＜0.01）. Microarray and pathway analysis revealed an upregulation of ECM components, but not growth factors or cytokines in Lhx2-deleted mice. In contrast, Lhx2 deletion in hepatocytes using Albumin-Cre had no effect on hepatocarcinogenesis thus excluding a role for Lhx2 in HCC or tumor-initiating cells. In summary, our genetic model suggests that HSC activation promotes HCC development, most likely through increased deposition ECM. Future studies are required to further determine which HSC-secreted factors promote HCC. |
